Turning Back Time
Imagine watching your child grow from infancy all the way into adulthood and then watching that same child cognitively regress from having a mature adult mind back into a child’s mind and eventually an infant’s mind. This is the situation that Tony and Christine Clark are going through with not one but two of their children, Michael (age 46) and Matthew (age 43), who are diagnosed with leukodystrophy.1 Leukodystrophy is a neurological disorder that results in symptoms that include cognitive degradation and motor deficiencies.2-4 There are a variety of types of leukodystrophy, each with their own unique characteristics.2,4 Unfortunately, since it is a rare disease, no cure has been discovered.2 Most of the research that is being done is to gain further understanding of the disease. In 2015, a research team in Montreal discovered mutations in a gene that affects about 10% of patients with the 4H leukodystrophy type.5 This recent breakthrough adds to their discovery in 2011 of two genes that are associated with 85% of cases with this type of leukodystrophy.5 These discoveries help create a path for possible treatments, and hopefully a cure.5 Due to the areas of the body it affects, leukodystrophy is a debilitating disorder that not only robs patients of having a future, but it also robs them of their present.
““Due to the areas of the body it affects, leukodystrophy is a debilitating disorder that not only robs patients of having a future, but it also robs them of their present.””
Leukodystrophy is a family of neurological disorders that destroys the white matter of a person’s brain, spinal cord and nerves, which ultimately causes their mental and physical decline and regression.2-4 White matter is composed of myelinated axons, which are responsible for transmitting signals throughout the body. These axons are insulated by myelin in order to ensure faster transmission of these important signals. However, with disorders like leukodystrophy that destroys myelin, patients experience declines in their mental and physical capabilities.2 Leukodystrophy is a progressive disorder by nature as the amount of white matter in a patient’s brain and nerves continually degrade.2,3 There are no distinct physical features that may indicate having the disorder, however there are symptoms that are common to all types of leukodystrophies.4 These common symptoms are gradual loss of mobility (due to spasticity and muscle weakness), balance, memory, hearing, speech, and the ability to eat.2-4,6 The severity of these symptoms varies depending on the type of leukodystrophy the patient has since each type affects the myelin sheath differently.2 Unfortunately, the motor deficiencies often mask the cognitive and behavioural symptoms that are also present. As a result, these cognitive and behavioural abnormalities often go unnoticed until the disease has progressed to a more severe stage.6 In the more severe stages of the disorder, patients experience developmental regression, which may cause them to behave and think like their childhood or infant selves, as in the case of Michael and Matthew Clark.4,7
““Leukodystrophy is a progressive disorder by nature as the amount of white matter in a patient’s brain and nerves continually degrade.””
After retiring early in 2005, Tony and Christine Clark moved from the UK to Spain and maintained contact with their children, Michael and Matthew, through frequent phone calls and text messages.1 The Clarks started to become suspicious that something was wrong when their two grown children stopped responding or contacting them back.1,8 Their suspicions were confirmed when they received a call from their granddaughter, Lydia, prompting them to come back to the UK.1,8 Upon coming back they saw that their sons, who look like grown men, were cognitively the children they remember raising 30 years earlier.1 Medical examinations of both men revealed that they have the rare, genetic neurological disorder of leukodystrophy.1
““Most patients with late infantile MLD pass away about five years after their symptoms appear.””
Leukodystrophy affects people of all ages and affects them in a variety of ways. Most types of leukodystrophies affect infants and children, with less types seen in adolescents and adults.2,4 In the case of the Clark brothers, the specific type of leukodystrophy they were diagnosed with was not publicized, but there are several types of leukodystrophy that appear in adulthood.1,2 Metachromatic leukodystrophy disorder (MLD) is one of the most common types of this rare disorder and, like all other types of leukodystrophy, it causes degradation of white matter in the brain, spinal cord and nerves.3,6 However, for this type of leukodystrophy the degradation of white matter is due to a deficiency of arylsulphatase A (ASA), which is responsible for degrading the fatty substance, sulfatide, which is found in the myelin sheath.2,6,9,10 Consequently, sulfatide accumulates in the brain, spinal cord and nerves among other parts of the body. This accumulation causes the demyelination of axons in the brain and peripheral neurons, which then cause the motor, cognitive and behavioural abnormalities that are associated with leukodystrophy.9,10 MLD is divided into three forms depending on the age of onset and the type of mutation the patient has: late infantile, juvenile and adult form.2,6,9,11 The late infantile form of MLD occurs in children four years old or younger with symptoms usually appearing between the first and second year of life.9-11 These patients have problems and delays achieving motor and cognitive milestones such as the ability to crawl, walk and talk and if they do, they gradually lose that ability as their disease progresses.9-11 In the later stages of this form, patients may experience seizures, blindness and dementia.9-11 Most patients with late infantile MLD pass away about five years after their symptoms appear.7,10,11 The juvenile form of MLD arises between the ages of 4 and 16 and is often first noticed when school performance starts to decline.9-11 Juvenile patients also experience problems with their fine motor skills and coordination.9-11 Patients usually live up to 10-15 years after symptoms appear.10,11 Finally, the adult form of MLD is diagnosed in patients older than 16 years old and has a slower progression than the other forms of MLD.9-11 Additionally, adult MLD is usually misdiagnosed for a psychiatric disease, therefore proper diagnoses and subsequent treatment, are less likely. Patients with this form of MLD may live for decades after being symptomatic due its slow progression.9,11 There are many types of leukodystrophy disorders and with each type, there are many subsets that depends on symptom severity, type of mutation and age of symptom onset.
““As Joe was approaching the start school, his parents were worried and watchful for the emergence of any signs of MLD.””
Similar to the Clarks, Nicola and Ian Elson have two children with leukodystrophy. Connie (age seven) and Joe (age five) Elson have both been diagnosed with MLD.7 The Elsons noticed that something was wrong with Connie soon after she started school when she became clumsier and had difficulties writing.7 The Elsons noticed that Connie was advanced for her age, reading and writing before starting school; thus, her decline was more pronounced to them.7 Due to the hereditary nature of the disease, the Elsons decided to test their youngest child, Joe, for the disorder. Unfortunately, Joe had the disorder as well but was still asymptomatic.7 As Joe was approaching the start school, his parents were worried and watchful for the emergence of any signs of MLD.7 Determined to treat Joe before he starts showing symptoms, the Elsons found a gene therapy trial in Italy for patients with MLD.7 Patients with MLD who were still asymptomatic were eligible to participate in the trial, therefore, Connie, unfortunately, was not.7 As of October of 2015, Joe just had his ninth month checkup and everything looked positive.7 His sister, who is no longer able to walk and talk, is currently going to a school for severely disabled children and still “seems very happy.”7
““Leukodystrophy is so rare that there is an even lesser chance of two carriers coming together.””
Leukodystrophy is a hereditary disorder in which the different types can be inherited through autosomal dominant, autosomal recessive and X-linked ways. MLD, which affects 1 in 160,000 people worldwide, is inherited through an autosomal recessive pattern.2,7,9-11 Leukodystrophy is so rare that there is an even lesser chance of two carriers coming together.7 Due to the genetic nature of the disease, leukodystrophy can be diagnosed by examining a person’s genes for mutations associated with it.4,9 This form of diagnosis can also be applied prenatally when parents either know they both have a defective copy of the gene or they already have a child with the disorder.9 When patients start experiencing the initial symptoms of leukodystrophy, a definitive diagnosis can be made through an MRI, which can display white matter deficiencies in a person’s brain, which is indicative of leukodystrophy.4,6,9 As demonstrated by the Elsons, early diagnosis is important since it gives patients and their families enough time to find experimental treatments.4,6 Since leukodystrophy has no cure, participating in promising experimental trials is the only hope some patients have in prolonging their life.4,6 Some of the experimental trials involves enzyme replacement, which could help patients with MLD due to the deficiency of ASA, bone marrow transplants, and gene therapy.4,6,9 Not all of these therapies will reach human trials, but they still pose significant risks and challenges.4 Patients also take medication to relieve pain and to decrease spasticity.2,9 Besides engaging in an experimental treatment, patients, especially those with a milder form, can undergo physical therapy, occupational therapy, and speech therapy.3 These therapies and the clinical trials that are available provide patients with leukodystrophy and their families hope for a cure in the future.
The Clark brothers and the Elson siblings have different types of leukodystrophies, but the disease has the same effect on them and their families as it robs them of a future and traps them in the past. Matthew and Michael’s physical features do not differ from their ages.1,8 Their behaviour, however, is similar to that of infants and children as they continually fight with each other and start to lose their autonomy, such as their ability to walk and feed themselves.1 Although they seem to be traveling back in time, their lives are still moving forward as Matthew is now a grandfather and their parents are getting older.1 Christine’s biggest fear is she and her husband passing away before their sons do because then she worries about them “having to survive” afterwards.1 The Clarks' situation is a unique one as the rare disease, leukodystrophy, is generally found to be more prevalent in infants and children.2,4 Thus, the Elsons’ case is more indicative of patients with leukodystrophy. Leukodystrophy is a family of rare hereditary diseases in which patients experience cognitive decline as well as motor deficiencies due to degradation of white matter in the brain, spinal cord, and nerves.2,4 Through advancements in medical technology, gene therapy is now an option for people who have a sibling or a child with leukodystrophy so that they can check whether they are carriers of a mutated gene or if their child has the disease before they become symptomatic.2,7,9-11 Through this form of early diagnosis, patients, like the Elsons, can look for possible therapies or experimental trials in which they may be able to benefit from.
Works Cited:
1. Moorhead J. The curious case of the boys who live backwards. Independent Website. http://www.independent.co.uk/life-style/health-and-families/health-news/the-curious-case-of-the-boys-who-live-backwards-8348395.html Published on November 24, 2012.
2. Leukodystrophy. NORD Website. http://rarediseases.org/rare-diseases/leukodystrophy/.
3. Leukodystrophy. GARD Website. https://rarediseases.info.nih.gov/diseases/6895/leukodystrophy Updated on January 1, 2016.
4. Kohlschutter A., Eichler F. Childhood leukodystrophies: a clinical perspective. Expert Rev. Neurother. 2011; 11(10): 1485-1496.
5. McGill University Health Centre. A glimmer of hope for patients with leukodystrophies. Eurekalert Website. https://www.eurekalert.org/pub_releases/2015-07/muhc-ago070815.php Published on July 8, 2015.
6. Aicardi, J. The Inherited Leukodystrophies: A Clinical Overview. Journal of Inherited Metabolic Disease. 1993; 16: 733.
7. Vale A. ‘Our children are counting on this new gene therapy treatment.’ The Telegraph Website. http://www.telegraph.co.uk/wellbeing/health-advice/children-family-health-genes-treatment/ Published on October 5, 2015.
8. Reilly J. Tantrums and tragedy: Brothers, 39 and 42, suffering from ‘Benjamin Button syndrom’ regress to the age of 10. Daily Mail Website. http://www.dailymail.co.uk/health/article-2137265/Tragic-brothers-39-42-suffering-Benjamin-Button-syndrome-regressed-age-10.html Updated on May 1, 2012.
9. Gieselmann V., Krageloh-Mann I. Metachromatic Leukodystrophy – An Update. Neuropediatrics. 2010; 41(1): 1-6.
10. Ikeda AK. Metachromatic Leukodystrophy. Medscape Website. http://emedicine.medscape.com/article/951840-overview Updated on August 21, 2014.
11. About MLD. ML Support Association UK Website. http://www.mldsupportuk.org.uk/about-mld/.
Cite This Article:
Macatangay K., Zheng K., Chan G., Ho J. Turning Back Time. Illustrated by H. Zhang. Rare Disease Review. January 2017. DOI:10.13140/RG.2.2.15340.77441.
